Marcus Smolka

Research Focus

Cell Signaling and Genome Maintenance: Damage to our genetic material is a threat to our survival and a driving force of many diseases. Our fundamental research interest is in the mechanisms of genome maintenance and we focus on the key roles of DNA damage checkpoint kinases (ATR, ATM, CHK1 and CHK2). We are using mass spectrometry technologies, in combination with genetic and biochemical approaches, to study the organization, dynamics and regulation of DNA damage signaling in yeast and humans.

DNA Replication Stress: We are particularly interested in understanding how cells respond to DNA replication stress, a major endogenous source of DNA damage that drives cancer progression. In addition to its role in causing cancer, replication stress is also used to cure cancer. For example, numerous anti-cancer agents such as topoisomerase inhibitors, DNA crosslinkers and DNA alkylators, kill cancer cells by impairing the regulated progression of the replication machinery and inducing replication stress. Despite the importance of this topic, the molecular circuitry that allows cells to respond to and resist replication stress is far from understood. We are particularly interested in understanding how checkpoint kinases function in response to replication stress, with the overall goal of elucidating the fundamental mechanisms of genome maintenance during DNA replication.

Phosphoproteomics: Reversible protein phosphorylation is widely used by cells as a signaling mechanism. Understanding the molecular basis of kinase action and function requires knowledge of the kinase substrates, as well as comprehensive characterization of the dynamics and role of the phosphorylation events. Because many kinases are active in a cell and thousands of proteins are phosphorylated, the study of phosphorylation-mediated signaling pathways is challenging and powerful technologies are needed. We have developed and applied quantitative mass spectrometry technologies for the phosphorylation analysis of protein complexes and for global screens of in vivo kinase substrates. We are now expanding the use of these technologies to quantitatively characterize signaling dynamics and regulation at a proteome-wide scale.